In the past decade, rapid development has occurred in the field of drug delivery and release. In particular, a number of drug delivery and release systems have been developed that influence the control of drug release.
For the topical treatment of diseases and disorders such as ulcerative colitis, drug release in the colon of the gastrointestinal tract topically accumulates the drug in a high concentration without involving absorption in the small intestine, which leads to the reduction of systemic side effects and is obviously favorable for the improvement of a therapeutic effect. Considering a systemic drug, on the other hand, release in the colon is disadvantageous in that the colon is shorter and poorer in development of microvilli than the small intestine and therefore has a smaller surface area available for absorption and is less permeable to a polar compound. However, the average retention time in the ascending colon is about 3 hours in younger people and about 10 hours in older people (Hongo et al., NICHIHEIKATSUKINSHI, 24:55-60 (1988)), which is equal to or even longer than that in the small intestine (about 3 to 4 hours), and it means a long, effective absorption time. Considering the aspect of the colon as a site of administration of peptide or protein-based drugs, the colon is advantageous in that no digestive enzymes are secreted and that the peptidase activity of the membrane of the large intestine is lower than that of the small intestine (Kopecek et al., Proc. Int. Symp. Control. Rel. Bioact. Mat., 17:130-131 (1990)). Therefore, drug release in the colon is expected to give improved systemic bioavailability.
A large number of preparations targeting the lower part of the gastrointestinal tract, especially the colon, have been reported. These systems are roughly divided into four types: (1) a delayed release system designed to release a drug in accordance with a change in pH; (2) a timed-release system designed to release a drug after a predetermined time; (3) a microflora enzyme system making use of the abundant enterobacteria in the lower part of the gastrointestinal tract; and (4) a system making use of a lectin-like substance specific to the large intestine.
The delayed release system uses an acrylic or cellulosic enteric coating material and dissolves on pH change. Because of ease of preparation, many reports on this system have been made. Taking the system using the acrylic enteric coating material Eudragit S as an example, many reports can be found, such as those by Behringer, Manchester University, Saale Co., and the like. However, the group from Manchester University reported at AAPS in 1993 that for such enterically-coated systems, the timing of drug release is determined by the transit of the system in the gastrointestinal tract rather than a pH change and, therefore, the specificity to the colon is low. Further, it is very likely that the other similar delayed release systems are also unsuccessful in colon-specific drug release.
The timed-release system is represented by the Time Erosion System (TES) from Fujisawa Pharmaceutical Co., Ltd. and Pulsincap from H. P. Scherer. According to these systems, the site of drug release is determined by the time of transit of the system in the gastrointestinal tract, which makes it difficult to target the release of a drug in the lower gastrointestinal tract. Since the transit of the system in the gastrointestinal tract is largely influenced by the gastric emptying time, some systems can be made with an enteric coating. Nevertheless, it is difficult to release a drug specifically in the colon, considering that the transit time of the system in the small intestine displays both intra- and inter-variation and also largely varies according to the disease or disorder to be treated.
Of particular interest is the system using the enterobacteria located in the lower gastrointestinal tract. This system is classified into three categories: (1) those utilizing degradation of azoaromatic polymers by an azo-reductase produced from enterobacteria as reported in Saffran et al., Science, 233:1081-1084 (1986) and Kopecek et al., Pharmaceutical Research, 9:1540-1545 (1992); (2) those utilizing degradation of polysaccharides by β-galactosidase of enterobacteria as reported in Japanese Patent Application No. 5-50863 and Bauer et al., Pharmaceutical Research, 10:5218 (1993); and (3) those utilizing degradation of chitosan by chitosanase as reported in Japanese Patent Application No. 4-217924 and Japanese Patent Application No. 4-225922. However, degradation of an azoaromatic polymer by enterobacteria is slow (Kopecek et al., supra) and may produce a harmful substance, making it unsuitable for long-term use. In fact, such a system containing insulin, when administered to beagle dogs, only achieved low efficacy (Saffran et al., Biochemical Society Transactions, 18:752-754 (1990)). The system using a polysaccharide is considered to cause no safety concerns because a material that has been taken as dietary fiber is used. However, according to a study performed by Cook et al., Pharmaceutical Research, 10:S223 (1993), the polysaccharide pectin is not only slowly degraded by enterobacteria, but the drug is released at a point in time prior to the arrival of the system in the colon. Therefore, this system appears to be ineffective as a colon-specific drug release system. Similarly, the drug release in artificial intestinal juice was found to be uncontrolled and non-specific (see, Japanese Patent Application No. 5-50863).
The system utilizing a lectin-like substance present in the large intestine has been reported in Kopecek et al., Proc. Int. Symp. Control. Rel. Bioact. Mat., 17:130-131 (1990). This technique relates to a polymeric system prepared by binding fucose and a drug to a polymer via an azo bond, utilizing a lectin-like substance present in the large intestine for fucose recognition, and controlling the transit of the system in the colon so as to let the system release the drug by the action of an azo-reductase. However, the fucose-recognizing lectin is specific only to guinea pigs. Therefore, the technique cannot be applied directly to humans.
As a result, none of the various systems described above for colonic drug release is satisfactory for providing site-specific drug release to the colon.
Another disadvantage of the various systems described above is the lack of sufficient pharmacological effects of the drug in the second half of the day from a system taken only once daily, especially for drugs where prolonged and consistent efficacy is required for effective treatment of a disease or disorder. In particular, delivery systems containing drugs that are quickly eliminated from plasma or have site-specific absorption patterns are confronted with the difficulty of maintaining effective levels over the period of a full day following oral administration. In general, such systems necessitate a dosing regimen where a patient is administered the drug at least twice a day. However, the inconvenience associated with multiple daily administrations, especially among children, leads to patient non-compliance and results in the ineffective treatment of a disease or disorder. As such, none of the above-described systems is suitable for providing sustained, site-specific drug release.
Thus, there is a need to develop a drug delivery system for the release of a drug in the gastrointestinal tract that provides, for example: (1) long-lasting drug efficacy (e.g., sustained release for about 24 hours); (2) site-specific delivery to multiple release sites (e.g., drug release in both the small intestine and colon); (3) reduced dosing frequency; and (4) drug release that is independent of the transit time of the system through the gastrointestinal tract. The present invention satisfies these and other needs.